Medicinal Products

ADVAGRAF 5 mg

Generic drug of the therapeutic class: Immunology
Active ingredients: Tacrolimus
laboratory: Astellas Pharma Europe BV

Sustained-Release Capsule
Box of 30
All forms

Indication

Prevention of graft rejection in adult renal or hepatic transplant patients.

Treatment of allograft rejection resistant to treatment with other immunosuppressive drugs in adult patients.

Posology ADVAGRAF 5 mg Prolonged-release capsule Box of 30

Advagraf is a once-a-day oral formulation of tacrolimus. Treatment with Advagraf requires close supervision by medical staff with the necessary skills and equipment. Only physicians familiar with immunosuppressive drugs and experienced in the management of transplant patients are able to prescribe this drug and initiate changes in immunosuppressive therapy.


Inadvertent, unintentional or unadvised substitution between tacrolimus-containing immediate-release and sustained-release formulations is risky. This may result in graft rejection or an increase in the incidence of adverse effects, including under-immunosuppression or over-immunosuppression, due to clinically significant differences in systemic exposure to tacrolimus. Patients should be maintained under the same formulation containing tacrolimus with the corresponding daily dosing regimen; the formulation or dosing schedule should only be changed under the close supervision of a transplant specialist (see sections Warnings and precautions for use and Adverse reactions ). Following conversion to any other formulation, therapeutic drug monitoring should be performed and dose adjustments initiated to maintain systemic tacrolimus exposure.


Dosage

The initial dosing recommendations presented below are for illustrative purposes only. Advagraf is generally given in combination with other immunosuppressive agents in the initial postoperative period. The dose may vary depending on the chosen immunosuppressive protocol. The dosage of Advagraf should be based primarily on the clinical evaluation of the signs of rejection and tolerance for each patient, aided by the monitoring of blood levels (see below "Drug Therapy Monitoring"). In the event of clinical signs of rejection, a modification of the immunosuppressive protocol should be considered.


In de novo renal and hepatic transplant patients, tacrolimus AUC 0- 24 for Advagraf on day 1 was, respectively, 30% and 50% lower than that obtained for immediate release capsule (Prograf) at equivalent doses. On the 4th day, the systemic exposure measured by the residual concentrations is similar in kidney transplant patients and in liver transplant patients with both formulations. Frequent and careful monitoring of residual concentrations of tacrolimus is recommended during the first two weeks after transplantation with A dvagraf to ensure adequate exposure to the drug in the immediate post-transplant period. Given the low clearance of tacrolimus, in case of dose adjustment, Advagraf's steady state may not appear until after several days.

Immunosuppression must be maintained to avoid rejection of the graft; therefore, no limitation of the duration of the oral treatment can be given.

Prevention of renal transplant rejection

Treatment with Advagraf will start at 0.20-0.30 mg / kg / day, once daily in the morning. Treatment should begin no later than 24 hours after transplantation.

In general, the dosage of Advagraf is reduced during the post-transplant period. It is possible in some cases to discontinue other concomitant immunosuppressive therapy and to use Advagraf as monotherapy. Changes in the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus and may require subsequent dose adjustments.


Prevention of hepatic graft rejection

Treatment with Advagraf will start at 0.10-0.20 mg / kg / day, once daily in the morning. Treatment should begin approximately 12 to 18 hours after transplantation.

In general, the dosage of Advagraf is reduced during the post-transplant period. It is possible in some cases to discontinue other concomitant immunosuppressive therapy and to use Advagraf as monotherapy. Improving the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus and may require subsequent dose adjustments.

Advagraf substitution of patients under Prograf

Advagraf substitution once daily in transplant patients maintained at the dosage of Prograf capsules twice daily should be based on a total daily dosage of 1: 1 (mg: mg). Advagraf should be given in the morning.

In stable patients converted from Prograf capsules (twice daily) to Advagraf (once daily) based on a total daily dosage of 1: 1 (mg: mg), systemic exposure to tacrolimus (AUC 0 -24 ) for Advagraf was about 10% lower than that of Prograf. The ratio of residual concentrations of tacrolimus (C 24 ) to systemic exposure (AUC 0-24 ) for Advagraf is similar to that of Prograf. When replacing Prograf capsules with Advagraf, the residual concentrations of tacrolimus must be measured before substitution and within two weeks of substitution. After substitution, residual concentrations of tacrolimus should be monitored and if necessary, dose adjustments should be made to maintain similar systemic exposure. Dose adjustments must be made to ensure that similar systemic exposure is maintained.


Replacement of ciclosporin with tacrolimus

Increased surveillance is recommended when replacing a ciclosporin-based protocol with a tacrolimus-based protocol (see sections Warnings and precautions for use and Interactions with other medicinal products and other forms of interaction ) . Concomitant administration of ciclosporin and tacrolimus is not recommended. Treatment with Advagraf should be initiated taking into account ciclosporin blood levels and the clinical status of the patient. Administration should be delayed in case of high blood concentrations of ciclosporin. In practice, tacrolimus therapy should be initiated 12-24 hours after discontinuation of ciclosporin. The monitoring of ciclosporin blood concentrations should continue after the substitution as the clearance of ciclosporin may be modified.

Treatment of allogeneic graft rejection

Increasing the dosage of tacrolimus, administering additional doses of corticosteroids, and introducing short courses of monoclonal or polyclonal antibodies have been used to treat rejection episodes. In case of signs of toxicity such as serious side effects (see section 4.8 ), it may be necessary to reduce the dose of Advagraf.

Treatment of allogeneic graft rejection after renal or hepatic transplantation If another immunosuppressant is switched from Advagraf once daily, treatment should begin at the recommended initial oral dose for the prevention of graft rejection, respectively in renal and hepatic transplantation. .

Treatment of allogeneic transplant rejection after cardiac transplantation

In adult patients converted to Advagraf, an initial oral dose of 0.15 mg / kg / day should be administered once daily in the morning.

Treatment of allogeneic graft rejection after transplantation of other grafts
Although there is no clinical experience with Advagraf in lung, pancreatic or intestinal transplantation, Prograf was used at initial oral doses of 0.10 - 0.15 mg / kg / day in lung transplantation, from 0, 2 mg / kg / day in pancreatic transplantation, and 0.3 mg / kg / day in intestinal transplantation.


Drug therapy monitoring

The dosage should be based primarily on clinical evaluation of the signs of rejection and tolerance for each patient using monitoring of residual concentrations of tacrolimus on whole blood.


To help optimize dosing, several immunoassay techniques are available to determine tacrolimus concentrations in whole blood. The comparison of the concentrations described in the literature with the individual values ​​observed in clinical practice should be evaluated with caution and taking into account the dosing method used. Currently, in clinical practice, monitoring of whole blood concentrations is performed by immunoassay methods. The ratio between residual concentrations of tacrolimus (C 24 ) and systemic exposure (AUC 0-24) is similar between the two Advagraf and Prograf formulations.


Residual whole blood concentrations of tacrolimus should be monitored posttransplantation. Blood levels of tacrolimus should therefore be determined approximately 24 hours after the last dose of Advagraf and just before the next dose. Frequent monitoring of residual levels during the first two weeks after transplantation is recommended, followed by regular monitoring during maintenance treatment. Residual concentrations of tacrolimus should also be closely monitored following Advagraf's substitution of Prograf for all dose adjustments, following changes in the immunosuppressive protocol, or after concomitant administration of substances that may affect whole blood concentrations of tacrolimus. tacrolimus (see section Interactions with other medicinal products and other forms of interaction ). The periodicity of concentration monitoring should be based on clinical status. Due to the low clearance of tacrolimus, in the case of Advagraf dosage adjustment, the target steady state may occur only after several days.


Data from clinical studies suggest that when residual blood concentrations of tacrolimus are kept below 20 ng / ml, the majority of patients can be treated effectively. It is necessary to consider the clinical condition of the patient when interpreting product concentrations in whole blood. In clinical practice, residual whole blood concentrations generally range between 5-20 ng / ml in liver transplant recipients and 10-20 ng / ml in renal and cardiac transplant patients in the immediate post-transplant period. During maintenance therapy, blood levels generally range from 5-15 ng / ml in liver, kidney and heart transplant recipients.

Special populations of patients Hepatic insufficiency

A dose reduction may be required in patients with severe hepatic impairment to maintain tacrolimus residual blood levels within the recommended range.

Renal failure

As the pharmacokinetics of tacrolimus are not affected by renal function (see section 5.2 ), no dose adjustment is required. However, due to the nephrotoxic potential of tacrolimus, it is recommended that renal function be closely monitored (including serum creatinine, creatinine clearance, and urinary flow monitoring).


Ethnic group

Compared to Caucasian patients, black patients may require higher doses of tacrolimus to achieve similar residual concentrations.


Sex

Currently available data do not show that men and women require different doses to achieve similar residual levels.


Older population

Currently available data do not show the need for dose adjustment in older populations.


Pediatric population

The safety and effectiveness of Advagraf in children under 18 years of age have not been established. Limited data are available but no dosage recommendations can be given.


Administration mode

Advagraf is an oral formulation of tacrolimus taken once daily. It is recommended to administer the daily oral dose of Advagraf once daily in the morning. Advagraf Prolonged-Release Capsules should be taken immediately after removal from the blister pack. Patients should be warned not to swallow the desiccant. The capsules should be swallowed whole with a liquid (preferably water). In general, Advagraf should be taken on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal to allow maximum absorption (see section Pharmacokinetic properties ). A missed dose in the morning should be taken as soon as possible on the same day. A double dose should not be taken the next morning.


For patients who can not take oral medications during the immediate posttransplantation period, tacrolimus therapy may be initiated intravenously (see Summary of Product Characteristics of Prograf 5 mg / ml concentrate for solution for infusion). the dose of approximately 1/5 th of the recommended oral dose for the corresponding indication.

Against indications

Hypersensitivity to tacrolimus or any of the excipients listed under Composition
Hypersensitivity to other macrolides

Advagraf side effects

The profile of adverse events associated with immunosuppressive therapy is often difficult to establish because of the underlying pathology and the concomitant use of many other drugs.

The most commonly reported adverse reactions (occurring in> 10% of patients) are tremor, renal function abnormalities, hyperglycemia, diabetes mellitus, hyperkalemia, infections, hypertension and insomnia.


The frequency of adverse events is defined as follows: very common (≥1 / 10); frequent (≥ 1/100, <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10 000, <1/1000); very rare (<1 / 10, 000), not known (can not be estimated based on available data). Within each frequency group, adverse effects should be presented in order of decreasing severity.


Infections and infestations

As with other potent immunosuppressants, patients receiving tacrolimus frequently have an increased risk of infections (viral, bacterial, fungal, protozoal). The evolution of pre-existing infectious diseases can be aggravated. Generalized or localized infections can develop.

Cases of BK virus nephropathy, as well as cases of JC virus progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Advagraf.


Benign, malignant and unspecified tumors

Patients receiving immunosuppressive therapy have an increased risk of developing malignant tumors. Both benign and malignant tumors, including EBV-associated lymphoproliferative syndromes and skin cancers, have been reported in connection with tacrolimus therapy.


Blood and lymphatic system disorders

Frequent: anemia, thrombocytopenia, leukopenia, erythrocyte abnormalities, leukocytosis
Uncommon: coagulopathies, pancytopenia, neutropenia, coagulation abnormalities and bleeding time
Rare: idiopathic thrombocytopenic purpura, hypoprothrombinemia
Not known: Acquired erythroblastopenia, Agranulocytosis, Haemolytic anemia


Immune system disorders

Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see Warnings and Precautions ).


Endocrine disorders
Rare: hirsutism


Metabolism and nutrition disorders

Very common: diabetes mellitus, hyperglycemia, hyperkalemia

Frequent: anorexia, metabolic acidosis, other electrolyte abnormalities, hyponatraemia, fluid overload, hyperuricemia, hypomagnesaemia, hypokalaemia, hypocalcemia, decreased appetite, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hypophosphatemia

Uncommon: dehydration, hypoglycemia, hypoproteinemia, hyperphosphatemia


Psychiatric disorders
Very common: insomnia

Common: confusion and disorientation, depression, signs of anxiety, hallucinations, mental disorders, depressed mood, mood disorders, nightmares
Uncommon: psychotic disorders


Nervous system disorders

Very common: headache, tremors

Frequent: disorders of the nervous system, convulsions, disturbances of consciousness, peripheral neuropathies, dizziness, paresthesia and dysesthesia, impaired writing

Uncommon: encephalopathy, central nervous system haemorrhage and stroke, coma, speech and language disorders, paralysis and paresis, amnesia

Rare: hypertonia

Very rare: myasthenia


Eye disorders

Common: eye disorders, blurred vision, photophobia

Uncommon: cataract
Rare: blindness


Affections of the ear and labyrinth

Frequent: Tinnitus

Uncommon: hypoacusis

Rare: sensorineural deafness

Very rare: hearing disorders


Heart conditions

Frequent: ischemic coronary artery disease, tachycardia

Uncommon: heart failure, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyopathies, ECG abnormalities, ventricular hypertrophy, palpitations, pulse and heart rate abnormalities

Rare: pericardial effusions

Very rare: echocardiogram abnormalities, QT elongation at electrocardiogram, torsades de pointes


Vascular disorders

Very common: hypertension

Frequent: thromboembolic and ischemic events, hypotensive vascular disorders,

hemorrhages, peripheral vascular disease
Uncommon: deep vein thrombosis of a limb, collapse, infarction


Respiratory, thoracic and mediastinal disorders

Frequent: pulmonary parenchymal disorders, dyspnea, pleural effusion, cough, pharyngitis, congestion and nasal inflammation
Uncommon: Respiratory failure, Respiratory tract disease, Asthma
Rare: acute respiratory distress syndrome


Gastrointestinal disorders

Very common: diarrhea, nausea

Gastrointestinal signs and symptoms, vomiting, gastrointestinal and abdominal pain, gastrointestinal inflammation, gastrointestinal haemorrhage, ulceration and perforation of the digestive tract, ascites, stomatitis and ulceration, constipation, dyspeptic signs and symptoms, flatulence, meteorism and bloating, loose stools

Uncommon: acute and chronic pancreatitis, peritonitis, hyperamylasemia, paralytic ileus, gastroesophageal reflux, gastric emptying

Rare: pancreatic pseudocyst, subtle

Hepatobiliary disorders

Very common: abnormal liver function tests

Frequent: biliary duct disorders, hepatocellular lesions and hepatitis, cholestasis and jaundice

Rare: hepatic veno-occlusive disease, thrombosis of the hepatic artery

Very rare: liver failure

Skin and subcutaneous tissue disorders

Frequent: rash, pruritus, alopecia, acne, sweating

Uncommon: dermatitis, photosensitivity

Rare: Bullous erythroderma with epidermolysis (Lyell's syndrome)

Very rare: Stevens-Johnson syndrome

Musculoskeletal and systemic disorders

Frequent: arthralgia, back pain, muscle cramps, limb pain

Uncommon: joint disorders

Renal and urinary disorders

Very common: renal function abnormalities
Common: renal failure, acute renal failure, toxic nephropathy, renal tubular necrosis, urinary disorders, oliguria, bladder and urethral symptoms

Uncommon: haemolytic uremic syndrome, anuria
Very rare: nephropathy, haemorrhagic cystitis

Disorders of reproductive organs and breast

Uncommon: dysmenorrhea and uterine bleeding

General disorders and administration site conditions

Frequent: fever, pain and discomfort, asthenia, edema, changes in the perception of body temperature, increased blood alkaline phosphatase, weight gain

Uncommon: weight loss, flu-like status, increased blood lactate dehydrogenase, feeling upset, feeling uncomfortable, multi-organ failure, chest tightness, intolerance to hot and cold

Rare: falls, ulcers, chest tightness, decreased mobility, thirst

Very rare: increase in adipose tissue

Injury, poisoning and procedural complications
Common: primary graft dysfunction

Medication errors, including inadvertent, unintentional or unadvised substitution between tacrolimus-containing sustained release and sustained release formulations, have been observed. A number of associated transplant organ rejection cases have been reported (frequency can not be estimated based on available data).

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals report any suspected adverse reactions via the national reporting system - see Annex V.

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